Dengue vaccine: WHO

position paper July 2016

Note de synthse de lOMS

sur le vaccin contre la dengue juillet 2016

Introduction

Introduction

In accordance with its mandate to provide

guidance to Member States on healthpolicy matters, WHO issues a series ofregularly updated position papers onvaccines and combinations of vaccinesagainst diseases that have an internationalpublic health impact. These papers aregenerally concerned with the use ofvaccines in large-scale immunizationprogrammes; they summarize essentialbackground information on diseases andvaccines, and conclude with the currentWHO position on the use of vaccinesworldwide.

The papers have been reviewed by external

experts and WHO staff, and are reviewedand endorsed by the WHO Strategic Advisory Group of Experts on Immunization(SAGE) (http://www.who.int/immunization/sage/en). The GRADE methodology is usedto assess systematically the quality of theavailable evidence. The SAGE decisionmaking process is reflected in the evidenceto-recommendation table.1 A description ofthe process followed for the developmentof vaccine position papers is available at:http://www.who.int/immunization/position_papers/position_paper_process.pdf.

The position papers are intended for use

mainly by national public health officialsandmanagersofimmunizationprogrammes. This paper is also intendedto provide information for nationaldengue control programmes. The vaccineposition papers may also be of interest tointernational funding agencies, vaccineadvisory groups, vaccine manufacturers,the medical community, scientific mediaand the general public.

This is the first WHO position paper on a dengue

vaccine. It focuses primarily on the available evidenceconcerning the only dengue vaccine to have been registered by National Regulatory Authorities (NRA). Recommendations on the use of this dengue vaccine werediscussed by SAGE in April 2016; evidence presented atthat SAGE meeting can be accessed at: http://www.who.int/immunization/sage/previous/en/index.html.

EpidemiologyThe number of dengue cases reported annually to WHOhas increased from 0.4 to 1.3 million in the decade19962005, reaching 2.2 million in 2010 and 3.2 millionin 2015.2, 3 There is substantial under-reporting ofdengue within health systems and to WHO.4 Based onmathematical modelling, the global annual incidencehas been estimated at about 50 million 100 millionsymptomatic cases in recent years, predominantly inAsia, followed by Latin America and Africa, with clinicalcases likely to represent about 25% of all dengue virusinfections.5, 6 In 2013 dengue was estimated to be responsible for approximately 3.2 million severe cases and 9000deaths, the majority occurring in lower middle incomecountries, and for 1.1 million disability adjusted lifeyears (DALYs) globally.5

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of dengue virus infections and cases. Country level data

on the epidemiology of dengue may mask substantialsubnational and local variability. Such heterogeneitycould be due to geographic factors, such as altitude, ordemographic factors, such as population density. Largedifferences in annual dengue incidence may be seen inneighbouring municipalities.8

PathogenDengue viruses are members of the genus Flavivirus,within the family Flaviviridae. There are 4 dengue virusserotypes (DEN-1, DEN-2, DEN-3 and DEN-4), all ofwhich circulate globally, with most endemic countriesreporting circulation of all 4 serotypes in recent years.9

Flaviviruses are lipid-enveloped, positive-sense, singlestranded RNA viruses. The structural premembrane(prM) and envelope (E) proteins are embedded in thelipid envelope and are displayed on the surface of virions. The 4 DEN serotypes share only about 60%75%identity at the amino acid level, and are thereforedistinct viruses.10

Upon human inoculation, the virus replicates in local

dendritic cells. Subsequent entry into macrophages andactivation of lymphocytes is followed by entry into thebloodstream. Dengue viruses primarily infect cells ofthe myeloid lineage, including macrophages, monocytes,and dendritic cells. There is evidence of infection ofhepatocytes and endothelial cells. Haematogenousspread is the likely mechanism for seeding of peripheralorgans and the occasionally reported infection of thecentral nervous system.

DiseaseThe majority of dengue virus infections are asymptomatic. For clinical cases the incubation period is usually47 days but can be in the range 314 days. The mostcommon presentation is the sudden onset of feveraccompanied by headache, retro-orbital pain, generalized myalgia and arthralgia, flushing of the face,anorexia, abdominal pain and nausea. Rash is frequentlyseen on the trunk, on the medial aspect of the armsand thighs, and on plantar and palmar surfaces and canbe macular, maculopapular, morbilliform, scarlatiniform or petechial. Laboratory-detected abnormalitiesmay include leukopenia and thrombocytopenia. Individuals infected multiple times with different denguevirus serotypes may experience multiple clinicalepisodes. There is no chronic infection with denguevirus or carriage state known.

There is no specific anti-viral treatment for dengue

illness. Clinical management is based on supportivetherapy, primarily judicious monitoring of intravascularvolume replacement. Improvements in case management have reduced the case fatality rate of hospitalizeddengue illness to less than 1%, whereas historically itwas as high as 20%.13, 14

Until the recent vaccine licensure, the only approach to

control or prevent the transmission of dengue virus wasthrough interventions targeting the vector, for whichWHO recommends integrated vector management.11Although many studies have shown reductions in entomological indicators following different forms of vectorcontrol, there is a paucity of data to show an impact ofthese interventions on the incidence of dengue illness.15

Naturally-acquired immunityImmune responses stimulated by natural exposure tobites of mosquitoes carrying dengue viruses are onlypartially understood and complicated by the inter-relatedness of host responses to the 4 distinct serotypes.Dengue virus infection induces high-titre neutralizingantibody, which is believed to be an important component of a protective immune response.16, 17 Following aprimary infection with one dengue virus serotype,protection against the infecting serotype (homotypicprotection) is considered long-lasting. Temporary crossprotection is induced to the other serotypes (heterotypic protection), lasting 2 years on average.18, 19 It iswell accepted that following waning of cross-neutralizing antibodies, severe illness is more likely to occurwith a second dengue virus infection than with the firstdengue virus infection [relative risk (RR)~7,20 althoughother studies have found higher21, 22 or lower23 RRs].Following recovery from a second infection, broadlyneutralizing antibodies are induced (multitypic protection), such that severe disease with subsequent infections is considered rare.24 The mechanism causinggreater severity of the second dengue virus infection isnot well understood although antibody-dependentenhancement, cytokine storm, or cross-reactive T cellshave been implicated in the pathogenesis.

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VaccinesOne dengue vaccine has been registered in severalcountries (CYD-TDV, or Dengvaxia); this is a live attenuated (recombinant) tetravalent vaccine. Several otherdengue vaccine candidates are in clinical development.After CYD-TDV, the 2 most advanced candidates are alsotetravalent live attenuated (recombinant) vaccines andare currently under evaluation in Phase 3 trials.25, 26WHO has developed recommendations to ensure thequality, safety, and efficacy of live attenuated tetravalentdengue vaccines.27

CYD-TDV has been evaluated in 2 parallel Phase 3

randomized clinical trials, known as CYD14 and CYD15.CYD14 was conducted at sites in 5 countries in Asia(Indonesia, Malaysia, Philippines, Thailand, and VietNam), with 10 275 participants aged 214 years at firstvaccination.28 CYD15 was conducted at sites in 5 countries in Latin America (Brazil, Colombia, Honduras,Mexico, and Puerto Rico (USA)), with 20 869 participants aged 916 years at first vaccination.29 In each ofthese trials, participants were randomized to receivevaccine or placebo (0.9% solution of sodium chloride)in a 2:1 ratio. The study protocols included activesurveillance for 13 months after the last dose of vaccinein the series (i.e. 25 months from dose 1) for the primaryefficacy endpoint and included a hospital-based surveillance period of 4 years for additional safety evaluation,which is ongoing.

Detailed analysis of the immune response, including an

assessment of the serological status at the time of studyenrollment, was conducted in a subset of both clinicaltrial cohorts. Participants with PRNT50 >10 against oneor more serotypes were considered seropositive at baseline, which was interpreted as evidence of previousexposure to at least 1 of the 4 dengue viruses.

Vaccine characteristics, content, dosage,

administration, storageCYD-TDV is a prophylactic, tetravalent, live attenuatedviral vaccine. The vaccination schedule consists of3injections of 0.5 mL administered at 6-month intervals. The indication from the first licenses is for theprevention of dengue illness caused by dengue virusserotypes 1, 2, 3, and 4 in individuals 945 years or960years of age (depending on the license), living indengue endemic areas. The lower limit of the indicationat 9 years of age was chosen due to a safety concern inchildren aged 25 years identified in the Phase 3 clinical trials (discussed under vaccine safety below).

CYD-TDV is available in a single-dose vial or in a multidose (5-dose) vial. It is a freeze-dried product to be

reconstituted before injection with either a sterile solution of 0.4% sodium chloride for the single-dose presentation or a sterile solution of 0.9% sodium chloride forthe 5-dose presentation. After reconstitution, the 0.5 mLdose is to be administered by the subcutaneous route.The diluent is provided as a pre-filled syringe forsingle-dose presentation or in a vial for the multi-dosepresentation. The CYD-TDV dengue vaccine contains noadjuvant or preservatives. The shelf-life of CYD-TDV is36months when stored between 2 C and 8 C. Afterreconstitution with the solvent provided, the vaccinemust be kept at between 2 C and 8 C and protectedfrom light. In accordance with the WHO multi-dose vialpolicy, any reconstituted doses remaining at the end ofthe session should be discarded within 6 hours of opening/reconstitution or at the end of a vaccination session,whichever comes first.30

The manufacturer stipulates that vaccination is contraindicated in: (1) individuals with a history of severeallergic reaction to any component of the denguevaccine or after prior administration of the denguevaccine or a vaccine containing the same components;(2) individuals with congenital or acquired immunedeficiency that impairs cell-mediated immunity;(3)individuals with symptomatic HIV infection or withasymptomatic HIV infection when accompanied byevidence of impaired immune function; (4) pregnant orbreastfeeding women; and that vaccination should bepostponed in individuals with moderate to severefebrile or acute disease.

ImmunogenicityThere is as yet no generally accepted correlate of protection induced by CYD-TDV, although a relationship hasbeen described between vaccine-induced neutralizingantibody titres and probability of virologicallyconfirmed dengue illness.31

Based on data collected from Phase 2 studies, following

2 doses the majority of seropositive subjects have atetravalent response.32 In seronegative subjects, theproportion with a tetravalent response is lower than inthe seropositive subjects. The 3-dose series increasedthe proportion of subjects with a tetravalent responseas compared to the 2-dose series, although many seronegative subjects still did not have a tetravalent responseafter 3 doses.32 However, seroconversion alone does notpredict protection. Additional investigations are ongoing to further characterize the relationship betweenimmunologic markers and protection against disease.

NRAs have approved the use of the product in individuals over 16 years of age, although vaccine efficacydata were available only up to 16 years of age. Safetyand immunogenicity studies were undertaken in 294individuals aged 1845 years in endemic settings.32, 33Although there is no correlate of protection that couldbe used for bridging beyond the age groups includedin the efficacy trials, it has been shown in Phase 2 studies that seropositivity at baseline is associated both withincreased age and with higher neutralization antibodytitres post vaccination. As efficacy was demonstrated inthose aged 916 years, it was predicted to be similar orbetter in adult populations living in endemic areas.

Vaccine efficacy estimates against virologicallyconfirmed dengue illness for all serotypes were similarin the per protocol analysis cited above and in theintent-to-treat (ITT) analyses starting from the firstdose.28, 29 The overall pooled estimate for CYD14 andCYD15 combined for virologically-confirmed dengueillness of any serotype in the 25 months post-dose 1(ITT) was 60.3% (95% CI 55.7%64.5%).35 Vaccine efficacy was lower in the youngest group aged 25 years(CYD14 only) at 33.7% (95% CI 11.7%50.0%), and washighest in the oldest age groups [74.4% (95% CI 59.2%84.3%) in CYD14 and 67.6% (95% CI 59.3%74.3%) inCYD15 among participants 1214 or 1216 years of age,respectively].28, 29 Vaccine efficacy was higher in individuals who were seropositive at baseline compared tothose who were seronegative at baseline, with pooledvaccine efficacies of 78.2% (95% CI 65.486.3) and 38.1%(95% CI -3.462.9), respectively.35 Age and seropositivitywere highly correlated in the trials.28, 29

The summary vaccine efficacy estimates reported above

have included children of all ages in the Phase 3 trials,including those <9 years of age who are not includedin the currently indicated age ranges. A post-hoc pooledanalysis limited to those >9 years of age in CYD14 andCYD15 was carried out. Pooled efficacy estimates in the25 months following dose 1 limited to participants aged9 years are similar to those for the full trial population. Vaccine efficacy was 65.6% (95% CI 60.7%69.9%)against virologically-confirmed dengue illness of anyserotype in the >9 years population, and in the subsetfor which baseline serostatus was assessed the efficacywas 81.9% (95% CI 67.2%90.0%) in those seropositiveat baseline and 52.5% (95% CI 5.9%76.1%) in thoseseronegative at baseline.35

Vaccine efficacy varied by country, with efficacy ranging

from 31.3% (95% CI 1.3%51.9%) in Mexico to 79.0%(95% CI 52.3%91.5%) in Malaysia.28, 29 This variabilityin efficacy likely reflects at least in part the baselineseropositivity and circulating serotypes, both of whichaffect the performance of the vaccine.

As completion of the 3-dose series in the Phase 3 trials

was very high (over 90%), efficacy after each dose couldnot be assessed, except in the 6 months following eachdose. In the pooled analysis in the indicated age range(916 years), vaccine efficacy between doses 1 and 2 was70.8% (95% CI 58.1%79.6%), between doses 2 and 3efficacy was 66.6% (95% CI 54.5%75.5%), and betweendose 3 and 6 months post-dose 3 efficacy was 62.4%(95% CI 51.4%70.9%).32 The protective effect of doses1 and 2 beyond 6 months after these doses is unknown,as is the additional protection derived from doses 2 and3. Second and third doses may influence the durationof efficacy and may have different effects in those seropositive or seronegative at baseline. These research gapsremain to be addressed.

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Vaccine efficacies against virologically-confirmed

dengue illness resulting in hospitalization or non-hospitalized severe dengue illness were higher in the25months following dose 1 than for virologicallyconfirmed dengue illness of any severity. Pooled vaccineefficacies against hospitalized dengue illness were 72.7%(95% CI 62.3%80.3%) and 80.8% (95% CI 70.1%87.7%)among participants of all ages and those 9 years,respectively.35 The corresponding pooled efficacy estimates against virologically-confirmed severe dengueillness were 79.1% (95% CI 60.0%89.0%) and 93.2%(95% CI 77.3%98.0%) among participants of all agesand those 9 years, respectively.35

Un risque accru dhospitalisation pour dengue a t identifi

Duration of protectionVaccine efficacy against virologically-confirmed dengueillness of any severity has been measured in the firstand second years post dose 1. Active surveillance iscurrently being re-initiated, so that vaccine efficacy56years post dose 1 can be evaluated.

Data on hospitalized dengue illness have been collected

throughout the trials, though with different surveillancesystems in different phases of the trial. These data werereviewed for assessment of protection during the duration of the Phase 3 trials. For hospitalized dengue illnessin ages included in the indication (916 years), the estimated yearly RR of hospitalized dengue illness typicallyremained below 1, suggesting a sustained protectiveeffect.32 In all age groups, the RR of severe dengueillness among vaccinated compared to controls waslower during the first 2 years of the trials than duringthe later years.36 These data may reflect potential waningof protection among all age groups.37

Vaccine safetyLocal and systemic adverse reactions following CYDTDV are comparable to those recorded for other liveattenuated vaccines. Safety data across multiple clinicaltrials that used the final formulation and final vaccination schedule have been pooled for the age range of960 years, both in endemic and non-endemic areas.38Solicited systemic reactions occurred in 66.5% of CYDTDV recipients compared to 59% of placebo recipients.32The most common solicited systemic reactions wereheadache (>50%), malaise (>40%), and myalgia (>40%).Fever occurred in 5% and 16% of participants in the

N. Ferguson Comparative modelling of dengue vaccine impact. Meeting of the Strategic Advisory Group of Experts (SAGE) on Immunization, 2016. Geneva, Switzerland. See slide 7, available at http://www.who.int/immunization/sage/meetings/2016/april/3_Ferguson_Comparative_Dengue_Modelling_SAGE.pdf?ua=1

CYD-TDV recipients aged 1860 years and 917 years,

malaises (>40%) et la myalgie (>40%). Parmi les participants

Approximately 10% of solicited systemic reactions were

Grade 3, mostly related to headache and fever. Solicitedinjection-site reactions occurred in 49.6% of CYD-TDVrecipients compared to 38.5% of placebo recipients.32Among solicited injection site reactions, the mostcommon was pain, reported by 45.2% of CYD-TDVrecipients aged 1860 years and 49.2% in those aged917 years. Of all solicited injection site reactions, <1%were Grade 3. In the Phase 3 trials, the number of serious adverse events was similar in the CYD and placebogroups (respectively 5% and 6% in CYD14, and 4.1%and 4.4% in CYD15).28, 29, 39 There is a hypothetical riskof acute viscerotropic or neurotropic disease due to theYF 17D backbone, but no cases have been detected todate.

During the course of the hospital-based surveillance, a

signal emerged from the youngest age group (25 years,an age group included only in CYD14). During both thefirst and second years post dose 1, the RR of hospitalized dengue illness between vaccine and placebo armsin the 25 year age group was 0.6 (not statisticallysignificant in either year).32 During the third year postdose 1, there were 15 hospitalized cases in the CYD-TDVgroup compared to 1 hospitalized case in the placebogroup (2:1 randomization), a RR of 7.5 (95% CI1.2313.8).35 During year 4 and year 5, the RRs diminished to 1.4 (95% CI 0.64.0) and 1.5 (95% CI 0.315.2),respectively.32 The cumulative RR during the entire trialperiod to date was greater than 1.3 (95% CI 0.82.1),not statistically significant. In contrast, among older agegroups (68, 911, and 1216 years), an increased riskof hospitalization was not seen consistently across thetrials. Similar patterns were seen for severe dengueillness, with a greater point-estimate in the hospitalbased surveillance phase for trial participants aged25years.32

The findings in children aged 25 years are unlikely to

be due to chance. Several hypotheses have beensuggested to explain the results, including that in seronegative children, of whom there is a higher percentagein the younger age groups, the vaccine may act as asilent natural infection that primes seronegative vaccinees to experience a secondary-like infection upon theirfirst exposure to dengue virus.40 Younger age (<5 years)may also contribute to the increased risk observed. Forthe indications, it was decided to exclude those aged68 years as a precautionary measure, and start theindicated age range at 9 years. Vaccination may be inef-

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fective or may theoretically even increase the future risk

of hospitalized or severe dengue illness in those whoare seronegative at the time of first vaccination regardless of age.41 If this is the case, even in high transmissionsettings there may be increased risk among seronegative persons despite a reduction in dengue illness at thepopulation level. Although data are limited by the trialdesigns, data collected from the immunogenicity subsetand followed over the 5 years of the ongoing Phase 3and Phase 2b trials did not show evidence of enhancedrisk in seronegative individuals 9 years of age, whereasthere was a suggestion of enhanced risk in seronegativechildren <9 years of age.32, 42

Co-administrationCo-administration studies previously conducted in children outside the indicated age range, in which CYDTDV was co-administered with YF vaccine, DTaP-IPV/Hib, and MMR, did not identify any safety concerns(data were comparable when vaccines were co-administered or given alone), and that the immunogenicityprofiles were satisfactory both for CYD-TDV and forco-administered vaccines.32, 43 A co-administration studywith YF vaccine in adults (for which the schedulediffered from the current 0/6/12 month schedule) identified a lower response to dengue serotype 4. Clinicaltrials are planned to assess safety and immunogenicitywith human papillomavirus (HPV) and tetanus toxoidand reduced-dose diphtheria (TdaP) vaccines inendemic settings.32

Estimation de limpact des programmes de vaccination

A comparison of several mathematical models of the

potential impact of CYD-TDV was carried out.40 Themodels assumed that (i) the vaccine mimics a silentnatural infection, providing temporary cross-protectionagainst all serotypes and (ii) subsequently modifies inthe long-term the likelihood of experiencing symptomatic and severe dengue according to previous exposureto dengue at the time of vaccination. The models alsoassumed that vaccination is implemented in settingswith existing dengue control interventions and treatment. With an assumed vaccine coverage of 80% for the3-dose series and vaccination at 9 years of age, allmodels found that deployment of CYD-TDV wouldresult in an overall reduction in dengue illness insettings with moderate to high transmission intensity(seroprevalence 50% at 9 years). The impact of vaccination was greatest in high transmission intensity

lence 70% 9 ans), o les modles prvoient une baisse de

All models predicted that in very low transmission

intensity settings (seroprevalence 10% at 9 years) vaccination of 9 year-olds was likely to increase denguehospitalization rates. Some models predicted the sameeffect when seroprevalence at 9 years was 30%. This wasdue to a key assumption used in the models, that vaccination acts like an asymptomatic natural infection andhence primes seronegative recipients to have a secondary-like infection when they are exposed to dengue forthe first time. In low transmission settings, where a highproportion of the population never experiences asecond dengue virus infection, vaccination could therefore lead to an increase in the incidence of dengueillness. The assumption on which this conclusion isbased cannot be confirmed or refuted by the clinicaltrial data collected to date, but it allows the models tomatch the currently available trial data.

Cost-effectivenessThe cost-effectiveness of CYD-TDV was assessed in themodelling comparison outlined above. Because the costof vaccine procurement and delivery was unknown, theanalyses were presented as costs per fully vaccinatedperson with CYD-TDV.40 One DALY averted was valuedin the base case at US$ 2000 based on benchmarkingthe costs against alternative intervention strategies toprevent dengue and alternative vaccines used in at leastsome dengue-endemic countries. Against this benchmark, in settings with seroprevalence at age 9 years inthe range 50%90%, vaccination was predicted to becost-effective using the public health payer perspectiveonly if the total cost of fully vaccinating one personwere less than US$ 1540, or, using a societal perspective, if the total cost of fully vaccinating one personwere less than US$ 100150. It should be noted, however,that the modelling comparison results were based onregional indicators and should not be used as a substitute for country-specific analyses to inform local decision-making.

Les pays devraient envisager lintroduction de vaccin CYD-TDV

In defining populations to be targeted for vaccination,

prior infection with dengue virus of any serotype, asmeasured by seroprevalence, should be approximately70% or greater in the age group targeted for vaccinationin order to maximize public health impact and costeffectiveness. Vaccination of populations with seroprevalence between 50% and 70% is acceptable but theimpact of the vaccination programme may be lower.The vaccine is not recommended when seroprevalenceis below 50% in the age group targeted for vaccination.

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The seroprevalence criteria for vaccine introduction are

based on the differential performance of CYD-TDV inseronegative compared to seropositive persons. Seroprevalence of 50% and above reflects the settings inwhich the Phase 3 clinical trials were conducted. Theoverall seroprevalence in trial participants aged916years in the Phase 3 studies was approximately80%. Use of CYD-TDV in populations in which seroprevalence is low in the age group considered for vaccination is not recommended because of low efficacy andpotential longer-term risks of severe dengue in vaccinated seronegative individuals. While age-stratifiedserosurveys are currently the best method for selectingpopulations suitable for vaccination, subnational, agestratified surveillance data may be used to help guidevaccine decision-making. Preferably a combination ofseroprevalence, surveillance data, and programmaticfactors should define the target population.

Dengue vaccine introduction should be a part of a

comprehensive dengue control strategy, including wellexecuted and sustained vector control, evidence-basedbest practices for clinical care for all patients withdengue illness, and strong dengue surveillance. Vaccineintroduction must be accompanied by a targetedcommunication strategy. Decisions about introductionrequire careful assessment at the country level, including consideration of local priorities, national andsubnational dengue epidemiology, predicted impact andcost-effectiveness with country-specific inputs, affordability and budget impact. At the time of introduction,countries are encouraged to have a functional pharmacovigilance system with at least minimal capacity tomonitor and manage adverse events following immunization.44 Countries considering vaccination should alsohave a dengue surveillance system able to detect andreport hospitalized and severe dengue cases consistently over time.

If CYD-TDV is introduced, it should be administered as

a 3-dose series given on a 0/6/12 month schedule.However, additional evidence is needed to determinewhether simplified schedules may elicit equivalent orbetter protection. Should a vaccine dose be delayed forany reason, the vaccine course should be resumed (notrestarted), maintaining the 6-month interval betweensubsequent doses. Because of the 12-month duration ofthe immunization schedule and to enable better vaccinemonitoring, countries should have systems in place fortracking vaccination.

World Health Organization. Global vaccine safety blueprint. Available at http://extranet.who.int/iris/restricted/bitstream/10665/70919/1/WHO_IVB_12.07_eng.

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current labelling. The target age for routine vaccination

should be defined by each country, based on maximizing vaccination impact and programmatic feasibility oftargeting specific age groups.45 Some countries mayexperience the highest incidence of dengue illnessamong adults and may consider vaccinating populations up to 45years of age in routine programmes.

Introduction of a routine CYD-TDV vaccination

programme at 9 years of age in settings meeting thecriteria outlined above is expected to result in a10%30% reduction in symptomatic and hospitalizeddengue illness over 30 years. Catch-up campaignstargeting older age groups may be considered if additional impact is desired and the additional costs can bemet, although most models predicted that a one-offcatch-up campaign for children aged 917 yearsprevented a similar number of symptomatic and hospitalized dengue cases per dose of vaccine delivered asin a routine vaccination programme at 9 years of age.40

Because the risk of immunological interference due to

co-administration of live with non-live vaccines isconsidered small, co-administration is permissible withthese and other non-live attenuated vaccines. Co-administration may be desirable to reduce programmaticcosts associated with school-based vaccinationprogrammes.46

CYD-TDV has not been studied as an intervention for

dengue outbreak control. Although the 3-dose vaccinemay be introduced during an outbreak as part of anoverall dengue control strategy, vaccination is notexpected to have a significant impact on the course ofthe ongoing outbreak. Any deployment of the vaccinein the context of an outbreak should only be done inareas that meet the recommended seroprevalence criteria for introduction of dengue vaccine in routineprogrammes.

There is presently no recommendation concerning

CYD-TDV in pregnant and lactating women due to lackof sufficient data in this population. However, thelimited data collected during the clinical trials on inadvertent immunization of pregnant women have yieldedno evidence of harm to the fetus or pregnant woman.32Women of child-bearing age who are targeted for vaccination do not need to be tested for pregnancy.

Until data become available from forthcoming studies

in HIV-infected individuals or other persons withimmune deficiency, there is no recommendationconcerning the use of CYD-TDV in HIV-infected orimmunocompromised individuals. There is no recommendation for vaccination of travellers or health-careworkers at this time.

For highly endemic settings (e.g. seroprevalence at 9 years of age of approximately

90% or greater), modelling predicts vaccination at 9 years of age will maximizeprogramme impact. In settings where seroprevalence at 9 years of age is between50% and 90%, higher impact may be achieved with vaccination at 1114 years ofage.

45

See Administration of multiple injectable vaccines in a single visit in Meeting of

the Strategic Advisory Group of Experts on immunization, April 2015: conclusionsand recommendations. Wkly Epidemiol Rec. 2015;90(22):261278.

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Dengue surveillance should be strengthened, particularly in the context of emerging infections with clinicalsimilarities to dengue and in areas of the world forwhich data are scarce or absent. Use of standardizedcase definitions is encouraged to enhance data sharingand comparability across regions. With the increase infalse-positive results from serological testing of CYDTDV vaccinated individuals,47 diagnostic testing shouldmove to virological confirmation whenever possible.

Important research and implementation questions

remain for CYD-TDV. Research on reduced or shorterinterval dosing schedules and safety in pregnant womenare high priorities. An approach to evaluate epidemiologic data based on high-quality age-stratified surveillance is needed to infer likely seroprevalence by age inorder to target vaccination efforts where seroprevalencedata are not available. As the vaccine is introduced inendemic countries, determination of vaccine effectiveness by dose and duration of protection and long-termimpact of vaccine programmes will be research priorities. However, it should be noted that using surveillancedata to monitor population impact of a vaccinationprogramme may be challenging as the year-to-year variability in dengue virus transmission may be greaterthan the expected vaccine impact on dengue illness.Special studies should be conducted to monitor theoccurrence over time of severe dengue illness in vaccinated persons, particularly among vaccinated seronegative persons.

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